We propose to continue studies of cholesterol synthesis in diabetes. In rats we will study the regulation of intestinal and hepatic HMG-CoA reductase, the rate limiting step in cholesterol biosynthesis, building upon the preliminary observation that diabetes increases intestinal reductase as it reduces hepatic reductase. We will consider the role of diet, bile acids and humoral factors, and will study the possibility that hepatic reductase is feedback inhibited by cholesterol synthesized in the gut. We will also study the effect of diabetes on non-sterol metabolism of mevalonic acid, to determine whether this pathway inversely correlates with, or even regulates, sterol synthesis. The net effect of these changes in reductase activity and non-sterol mevalonate metabolism will be observed by measuring whole body cholsterol synthesis using 3H2O as a precursor. In human diabetics, we will test the effect of varying plasma glucose and insulin, controlled within narrow limits by an artificial pancreas, on cholesterol synthesis as estimated by isotopically labeled squalene kinetics. Finally, in rats and humans, we will test the utility of lymphocyte HMG-CoA reductase as an indication of whole body cholesterol synthesis. We expect these studies to shed light on the mechanisms regulating cholesterol synthesis, how they are perturbed by diabetes, and ultimately how atherosclerosis is accelerated in diabetes.